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Recent evidence suggests that complex karyotype (CK) defined by the presence of ≥3 chromosomal aberrations (structural and/or numerical) identified by using chromosome-banding analysis (CBA) may be relevant for treatment decision-making in chronic lymphocytic leukemia (CLL). However, many challenges toward the routine clinical application of CBA remain. In a retrospective study of 5290 patients with available CBA data, we explored both clinicobiological associations and the clinical impact of CK in CLL. We found that patients with ≥5 abnormalities, defined as high-CK, exhibit uniformly dismal clinical outcomes, independently of clinical stage, TP53 aberrations (deletion of chromosome 17p and/or TP53 mutations [ TP53 abs]), and the expression of somatically hypermutated (M-CLL) or unmutated immunoglobulin heavy variable genes. Thus, they contrasted with CK cases with 3 or 4 aberrations (low-CK and intermediate-CK, respectively) who followed aggressive disease courses only in the presence of TP53 abs. At the other end of the spectrum, patients with CK and +12,+19 displayed an exceptionally indolent profile. Building upon CK, TP53 abs, and immunoglobulin heavy variable gene somatic hypermutation status, we propose a novel hierarchical model in which patients with high-CK exhibit the worst prognosis, whereas those with mutated CLL lacking CK or TP53 abs, as well as CK with +12,+19, show the longest overall survival. Thus, CK should not be axiomatically considered unfavorable in CLL, representing a heterogeneous group with variable clinical behavior. High-CK with ≥5 chromosomal aberrations emerges as prognostically adverse, independent of other biomarkers. Prospective clinical validation is warranted before ultimately incorporating high-CK in risk stratification of CLL., (© 2019 by The American Society of Hematology.)

Karyotype according to the revised IPSS is a strong independent prognostic factor for overall survival (OS) in myelodysplastic syndromes (MDS), however established in untreated patients. The prognostic impact of cytogenetics and cytogenetic response (CyR) in MDS patients receiving azacitidine (AZA) remains uncertain. We examined the prognostic value of baseline cytogenetics and CyR for overall response rate (ORR) and OS in 702 AZA-treated higher risk MDS and low blast count acute myeloid leukemia (AML), including 493 (70%) with abnormal karyotype. None of the cytogenetic abnormalities had significant impact on ORR (43.9%) or complete response (15.35%), except 3q abnormalities and complex karyotypes, which were associated with a lower ORR. OS differed significantly across all R-IPSS cytogenetic subgroups (p<10 -4 ) but patients with non complex del(7q) had similar survival as patients with normal cytogenetics. CyR was achieved in 32% of the 281 evaluable patients with abnormal cytogenetics, was complete (CCyR) in 71 (25.3%) patients. We found no correlation between hematological response and cytogenetic response and 21% of the patients with CCyR did not achieve morphological response. In the 281 patients, we found no impact of CyR on survival, but when restricting to MDS (ie: <20% marrow blasts) achievement of CCyR was associated with better OS., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Multiple cytogenetic subgroups have been described in adult Philadelphia chromosome (Ph)-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL), often comprising small numbers of patients. In this study, we aimed to reassess the prognostic value of cytogenetic abnormalities in a large series of 617 adult patients with Ph-negative BCP-ALL (median age, 38 years), treated in the intensified Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/2005 trials. Combined data from karyotype, DNA index, fluorescence in situ hybridization, and polymerase chain reaction screening for relevant abnormalities were centrally reviewed and were informative in 542 cases (88%), allowing classification in 10 exclusive primary cytogenetic subgroups and in secondary subgroups, including complex and monosomal karyotypes. Prognostic analyses focused on cumulative incidence of failure (including primary refractoriness and relapse), event-free survival, and overall survival. Only 2 subgroups, namely t(4;11)/ KMT2A-AFF1 and 14q32/ IGH translocations, displayed a significantly worse outcome in this context, still observed after adjustment for age and after censoring patients who received allogeneic stem cell transplantation (SCT) in first remission at SCT time. A worse outcome was also observed in patients with low hypodiploidy/near triploidy, but this was likely related to their higher age and worse tolerance to therapy. The other cytogenetic abnormalities, including complex and monosomal karyotypes, had no prognostic value in these intensive protocols designed for adult patients up to the age of 60 years., (© 2017 by The American Society of Hematology.)

Waldenström's macroglobulinemia is a disease of mature B cells, the genetic basis of which is poorly understood. Few recurrent chromosomal abnormalities have been reported, and their prognostic value is not known. We conducted a prospective cytogenetic study of Waldenström's macroglobulinemia and examined the prognostic value of chromosomal aberrations in an international randomized trial. The main aberrations were 6q deletions (30%), trisomy 18 (15%), 13q deletions (13%), 17p (TP53) deletions (8%), trisomy 4 (8%), and 11q (ATM) deletions (7%). There was a significant association between trisomy of chromosome 4 and trisomy of chromosome 18. Translocations involving the IGH genes were rare (<5%). Deletion of 6q and 11q, and trisomy 4, were significantly associated with adverse clinical and biological parameters. Patients with TP53 deletion had short progression-free survival and short disease-free survival. Although rare (<5%), trisomy 12 was associated with short progression-free survival. In conclusion, the cytogenetic profile of Waldenström's macroglobulinemia appears to differ from that of other B-cell lymphomas. Chromosomal abnormalities may help with diagnosis and prognostication, in conjunction with other clinical and biological characteristics.

Isolated 20q deletion is common in MDS and considered of good prognosis, but no large series have been reported. We compared characteristics of 62 MDS patients with isolated del 20q, 36 patients with del 20q and other cytogenetic abnormalities, and 1335 MDS patients without del20q. Significant differences between MDS with isolated del 20q and patients without del 20q were lower platelet count (mean 144 vs. 196 G/l, p=0.005), lower marrow blast count (mean 3.9% vs. 5.6%, p=0.0008), and higher reticulocyte count (mean 72.5 vs. 51.7 G/l, p=0.04). Ten (16%) patients with isolated del 20q had Hb>12 g/dl and platelets <100 G/l, compared to 7.3% of patients without del 20q (p=0.025). Review of marrow slides of those 10 patients showed that could be readily identified as MDS prior to cytogenetics. Fourteen percent of patients with isolated del 20q progressed to AML compared to 11% with one and 24% with several additional abnormalities. Median survival was 54 months in patients with isolated del 20q, not reached and 12 months for del 20q with one and several additional abnormalities, respectively (p=0.035) confirming the favorable prognosis of del 20q without complex abnormalities., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Evolution to myelofibrosis (MF), acute myeloid leukemia or myelodysplastic syndrome (AML/MDS) may occur over time in myeloproliferative neoplasms (MPN) patients most likely due to the acquisition of additional mutations. The Groupe Francophone de cytogenetique hematologique (GFCH) has collected and reviewed 82 patients with transformation of MPN (66 AML/MDS and 16 MF). JAK2V617F and TET2 mutations were searched for in 40 and 32 patients, respectively. Significantly more -7/del(7q) (P = 0.004) and -5/del(5q) (P = 0.03) were found in AML/MDS with a higher incidence of dup1q (P = 0.01) in MF. Some specific chromosomal abnormalities occurred together, for example -5/del(5q) and -17/del(17p) (P = 0.0007). In multivariate analysis, two factors were independently associated with an inferior overall survival (OS); AML/MDS transformation (P < 0.0001) and -5/del(5q) abnormality (P = 0.02). Although both giving rise to loss of 7q, der(1;7) differed from other 7q deletions in terms of distribution (lower frequency of AML/MDS, P = 0.02), association with chromosomal abnormalities (absence of -5/del(5q), P = 0.003; increased del(20q), P = 0.05), and longer OS (P = 0.0007). We detected 24/40 (60%) JAK2V617F and 8/25 (32%) TET2 mutations in samples following transformation, ranging from wild-type to mutated forms of both genes. The mutated and wild-type forms of the genes were not found to be associated with a specific chromosomal abnormality. There was no evidence that JAK2 or TET2 mutations were associated with the type of MPN transformation, whereas the type of cytogenetic abnormalities were strongly linked, perhaps indicating that they play a specific role in the transformation process.

In chronic myeloid leukemia (CML), cytogenetic abnormalities found in addition to the t(9;22) translocation may impact the response to therapy. Loss of the Y chromosome is generally overlooked in this context, owing to its relatively frequent occurrence in healthy elderly patients. In this multicenter retrospective study, the outcome after imatinib treatment of 30 CML patients with karyotype showing Y chromosome loss (Y-) was compared to 30 Y+ control males diagnosed and treated at the same time in the same institutions. Y- patients had significantly delayed cytogenetic and molecular responses, lower event-free survival and shorter overall survival than Y+ patients. The negative impact of this abnormality was particularly marked when it occurred in a sub-clone (clonal evolution) rather than in all mitoses. These data indicate that loss of the Y chromosome should be taken into account in the prognostic evaluation of chronic myelogenous leukemia patients.

B-cell chronic lymphocytic leukemia (CLL) follows a heterogeneous clinical course, for which several biological markers may predict clinical outcome. Cytogenetic aberrations are considered major prognostic indicators for predicting the survival of CLL patients. Given the difficulties in obtaining abnormal metaphases in CLL, fluorescent in situ hybridization (FISH) with specific probes is generally used to detect the most frequent abnormalities. To determine the best strategy for identifying cytogenetic abnormalities, we compared results obtained by FISH analysis on peripheral blood mononuclear cells with those obtained by FISH after culture with mitogens. We studied 46 CLL patients selected from two different institutions. The most frequent structural aberrations leading to loss of genetic material were loss of the 13q14 region, in 32 cases (70%), and loss of TP53 in 11 cases (24%). Of the 46 cases patients, 10 patients (21.7%) had deletion of the ATM locus at 11q22 and 8 patients (17%) had trisomy 12. Results could be interpreted as discordant in four cases in which the abnormal clone was small and both values were around the threshold. FISH performed on stimulated cells detected the same frequency of abnormalities as FISH performed without culture. This equivalence between the two techniques allows performing both conventional cytogenetic and FISH analyses on the same sample.

CD4(+), CD56(+) DC2 malignancies constitute a novel disease entity, which has recently been shown to arise from a transformed lymphoid-related plasmacytoid dendritic cell (DC2). Diagnosis is primarily based on a particular immunophenotype with tumor cells expressing CD4 and CD56 antigens in the absence of common lymphoid or myeloid lineage markers. Little is currently known about the cytogenetic features of this disease entity. In this setting, the Groupe Français de Cytogénétique Hématologique (GFCH) initiated a cytogenetic study of 18 adults and 3 children with CD4(+), CD56(+) DC2 acute leukemia using conventional and fluorescence in situ hybridization/24-color karyotyping. Clonal, mostly complex chromosome aberrations were found in 14 patients (66%). Six major recurrent chromosomal targets were defined. These were 5q, 12p, 13q, 6q, 15q, and 9, which were involved in 72% (5q), 64% (12p and 13q), 50% (6q), 43% (15q), and 28% (monosomy 9) of cases, respectively. Cytogenetic features can be summarized as follows: (1) gross genomic imbalances (mostly losses) predominate, (2) no single anomaly can be considered as specific, whereas their combination/accumulation is, and (3) both lymphoid and myeloid lineage-associated rearrangements are observed in unusual combinations in the same cell. This is suggestive of complex multistep tumorigenic mechanisms and is supportive of the hypothesis that CD4(+), CD56(+) DC2 acute leukemia may arise from an undifferentiated nonmyeloid nonlymphoid progenitor cell. In conclusion, the present study documents for the first time the existence of a characteristic cytogenetic profile for this novel disease entity.